The expanding population of aging adults is predicted to create a large public health burden in the next few decades. Older humans also exhibit reduced exercise capacity and lower muscle blood flow during exercise. The overall goal of this research program is to investigate the age-induced changes in microvascular structure, function and protein expression contributing to impaired muscle blood flow in older adults. This proposal seeks to directly test vascular control in human skeletal muscle resistance arteries (RAs) from quadriceps of young and older (e60 years) adults. The general hypothesis is that endothelium dependent dilation (EDD) is impaired via reductions in nitric oxide (NO) bioavailability and a shift away from cyclooxygenase (COX)-derived vasodilator prostaglandins (PGs) to increased vasoconstrictor PGs. This shift is due in part to increases in oxidative stress. These observations were made in resting forearms, so it remains unknown whether vascular dysfunction is occurring in the leg of older adults. The methods employed to address these aims involve muscle biopsies to investigate mechanisms that control of resistance arteries from young and older healthy humans. We have several exciting preliminary findings that support our hypotheses, and lay the groundwork for a complete R01 application in 1-2 years. The findings from these studies will provide novel insight into the regulation of muscle blood flow and vascular control in aging humans, and also could provide treatment interventions to improve muscle blood flow and exercise intolerance in diseased populations that also demonstrate endothelial dysfunction (e.g., diabetics or hypertensives). PUBLIC HEALTH RELEVANCE: Aging adults exhibit poor exercise capacity which reduces quality of life and increases cardiovascular risk. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to limitations in blood flow and therefore exercise intolerance in older adults. The findings of how aging changes blood vessel function and protein expression will provide ideas on how to prevent or improve function, in an effort to restore the quality of life of older adults. The findings from these studies will provide novel insight into the regulation of muscle blood flow and vascular control in aging humans, and also could provide treatment interventions to improve muscle blood flow and exercise intolerance in diseased populations that also demonstrate poor blood vessel function (e.g., diabetes or high blood pressure).